Obesity and its metabolic complications are highly prevalent and are major health problems in the United States and worldwide. Indeed, obesity may influence individual susceptibility to other environmental exposures such as vinyl chloride (VC). Specifically, we hypothesize that experimental NAFLD and the consumption of certain types of dietary fat such as poly-unsaturated fatty acids (PUFA) sensitize the liver to VC as a 2nd hit. We therefore propose that that LA metabolites sensitize the liver to VC hepatotoxicity via molecular, organelle, and cellular VC effects (NAFLD mechanisms).
Aim 1. Evaluate the role of OXLAMs in VC-enhanced hepatocyte death in an animal model of NAFLD. Specifically, we will: a) determine the dose response for NAFLD/NAFLD mechanisms following sub-acute VC exposures and the impact of co-exposures with HF/LA diets, b) determine whether the ablation of OXLAMs via 12/15-LO genetic deficiency attenuates VC-induced liver inflammation and injury and the mechanisms involved. This work will be performed in vivo comparing wild-type (WT) to 12/15-LO knockout mice with complementary in vitro models that target 12/15-LO pharmacologically or genetically (e.g., primary cells derived from 12/15-LO KO mice). Mechanistic endpoints based on preliminary data will include mitochondrial dysfunction, hepatocyte death (necrosis vs. apoptosis), ER stress and metabolism/ bioenergetics impacting steatosis/cell survival.
The aims of this R03 build on my K01 research and extend that project. However, here we are building on that foundation to leverage new questions in investigating the role of a specific fat type (and its oxidized metabolites) that is prevalent in the US. This focus is distinct and unique from my K01 research, but will complement it very aptly. This proposal is consistent with the goals of NIDDK to investigate the causes/consequences of obesity.

Public Health Relevance

We propose that vinyl chloride exposure, even below levels that are overtly hepatotoxic, may increase the stimulated inflammatory response in the liver, potentially adding another risk factor to the development of liver disease associated with diet induced obesity (i.e., non-alcoholic fatty liver disease). The project will focus on the interaction of vinyl chloride and specific dietary fatty acids in experimental NAFLD.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
Project #
Application #
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Saslowsky, David E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Liang, Yaqin; Lang, Anna L; Zhang, Jian et al. (2018) Exposure to Vinyl Chloride and Its Influence on Western Diet-Induced Cardiac Remodeling. Chem Res Toxicol 31:482-493
Lang, Anna L; Chen, Liya; Poff, Gavin D et al. (2018) Vinyl chloride dysregulates metabolic homeostasis and enhances diet-induced liver injury in mice. Hepatol Commun 2:270-284
Lang, Anna L; Beier, Juliane I (2018) Interaction of volatile organic compounds and underlying liver disease: a new paradigm for risk. Biol Chem 399:1237-1248
Beier, Juliane I; Banales, Jesus M (2018) Pyroptosis: An inflammatory link between NAFLD and NASH with potential therapeutic implications. J Hepatol :
Guardiola, John J; Beier, Juliane I; Falkner, K Cameron et al. (2016) Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome. Toxicol Appl Pharmacol 313:47-56
Beier, Juliane I; Guo, Luping; Ritzenthaler, Jeffrey D et al. (2016)  Fibrin-mediated integrin signaling plays a critical role in hepatic regeneration after partial hepatectomy in mice. Ann Hepatol 15:762-72
Anders, Lisanne C; Yeo, Heegook; Kaelin, Brenna R et al. (2016) Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice. Toxicol Appl Pharmacol 311:34-41
Kirpich, Irina A; Petrosino, Joseph; Ajami, Nadim et al. (2016) Saturated and Unsaturated Dietary Fats Differentially Modulate Ethanol-Induced Changes in Gut Microbiome and Metabolome in a Mouse Model of Alcoholic Liver Disease. Am J Pathol 186:765-76
Anders, Lisanne C; Lang, Anna L; Anwar-Mohamed, Anwar et al. (2016) Vinyl Chloride Metabolites Potentiate Inflammatory Liver Injury Caused by LPS in Mice. Toxicol Sci 151:312-23